U.S. Pat. No. 5,245,053, the disclosure of which is incorporated herein by reference, describes a series of 1,3-benzodioxoles useful in the treatment of diabetes and hyperglycemia, of which (R,R)-(-/-)-5-[2-{2-(3-chlorophenyl)-2-hydroxyethyl}aminopropyl]-1,3-benzo dioxole-2,2-dicarboxylic acid, its esters, and salts are representative.
Other pharmacological agents described in the literature also contain the N-(2-phenyl-2-hydroxyethyl)-2-aminopropylphenyl structure, as for example, 2-[2-(3-chlorophenyl)-2-hydroxyethyl]-1-(4-carbomethoxyphenyl)-2-[2-(3-chl orophenyl)-2-hydroxyethyl]aminopropane {BRL 26830}; 1-(4-methoxycarbonylmethoxyphenyl)-2-[2-(3-chlorophenyl)-2-hydroxyethyl]am inopropane {BRL 35135}; and N,N-bis-{2-[2-(3-chlorophenyl)-2-hydroxyethyl]}-1-(4-[2-ethoxyethoxy]pheny l)-aminopropane {Ro 40-2148}.
These compounds, which possess at least two centers of chirality, can be prepared through a variety of multistep syntheses. In one embodiment for the preparation of (R,R)-(-/-)-5-[2-{2-(3-chlorophenyl)-2-hydroxyethyl}aminopropyl]-1,3-benzo dioxole-2,2-dicarboxylic acid characterized in U.S. Pat. No. 5,245,053 as preferred, the synthesis begins with the reductive amination of a 3,4-dimethoxyphenylacetone to with 2-phenyl-2-hydroxyethylamine to afford an N-(2-phenyl-2-hydroxyethyl)-1-(3,4-dimethoxyphenyl)prop-2-ylamine. This initial intermediate, which already possesses the two chiral centers of the final product, is treated with carbonyl diimidazole to afford isomeric 3-[1-(3,4-dimethoxyphenyl)prop-2-yl]-5-phenyloxazolidin-2-ones which then are separated by derivatization, chromatography, and regeneration to isolate the desired (R,R)-diastereoisomer. Only the thusisolated (R,R)-diastereoisomer is subjected to the subsequent synthetic steps to produce the final compounds, unwanted isomeric material presumably being discarded.